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Subclonal diversification of primary breast cancer revealed by multiregion sequencing
npg 201 5 Nature America, Inc. All rights reserved.
Lucy R Yates1,2, Moritz Gerstung1, Stian Knappskog3,4, Christine Desmedt5, Gunes Gundem1, Peter Van Loo1,6, Turid Aas7, Ludmil B Alexandrov1,8, Denis Larsimont5, Helen Davies1, Yilong Li1, Young Seok Ju1,
Manasa Ramakrishna1, Hans Kristian Haugland9, Peer Kaare Lilleng9,10, Serena Nik-Zainal1, Stuart McLaren1, Adam Butler1, Sancha Martin1, Dominic Glodzik1, Andrew Menzies1, Keiran Raine1, Jonathan Hinton1, David Jones1, Laura J Mudie1, Bing Jiang11, Delphine Vincent5, April Greene-Colozzi11, Pierre-Yves Adnet5, Aquila Fatima11, Marion Maetens5, Michail Ignatiadis5, Michael R Stratton1, Christos Sotiriou5,
Andrea L Richardson11,12, Per Eystein Lnning3,4, David C Wedge1 & Peter J Campbell1
The sequencing of cancer genomes may enable tailoring of therapeutics to the underlying biological abnormalities driving a particular patients tumor. However, sequencing-based strategies rely heavily on representative sampling of tumors. To understand the subclonal structure of primary breast cancer, we applied whole-genome and targeted sequencing to multiple samples from each of 50 patients tumors (303 samples in total). The extent of subclonal diversification varied among cases and followed spatial patterns. No strict temporal order was evident, with point mutations and rearrangements affecting the most common breast cancer genes, including PIK3CA, TP53, PTEN, BRCA2 and MYC, occurring early in some tumors and late in others. In13 out of 50 cancers, potentially targetable mutations were subclonal. Landmarks of disease progression, such as resistance to chemotherapy and the acquisition of invasive or metastatic potential, arose within detectable subclones of antecedent lesions. These findings highlight the importance of including analyses of subclonal structure and tumor evolution in clinical trials of primary breast cancer.
or confer metastatic capacity. In colon, pancreatic and hematological cancers, preferred temporal orders of somatic mutation accumulation may predominate1215, but whether this applies to breast cancer has not been evaluated. In renal, pancreatic, colon and prostate tumors, geographical stratification of clonal structure is common, with subclones containing driver mutations expanding locally1621.
Whether early breast cancers show similar patterns is unknown.
RESULTSMultiregion sequencing of breast cancer
To determine the patterns of spatial evolution in primary breast cancer, we sequenced multiregion samples from 50 invasive cancers (27 positive for estrogen receptor (ER) expression but negative for HER2 expression (ER+HER2); 3 ER+HER2+; and...